Maternal drug addiction constitutes a major public health problem for both women and affected children, with long lasting consequences on children's social, emotional and cognitive development. Current treatment strategies tend to focus on the mother and her current addiction, rather than her relationship with her child, and developmental processes that may perpetuate the addiction problems, such as unresolved childhood attachment trauma, neglect, and chronic stress. Unlike mothers who find engaging with their own infant to be a uniquely rewarding experience, mothers with addictions may be less able to respond appropriately to their infant's cues, finding them less intrinsically rewardin or salient, and more stress provoking. Our current study has identified key areas in dopaminergic and oxytocinergic brain pathways that show a diminished functional MRI response when addicted mothers view the faces of their own vs. unknown infants, compared with non- addicted mothers. These areas include the hypothalamus, striatum and ventromedial prefrontal cortex. Oxytocin, a neuropeptide with decreased peripheral levels seen in addicted mothers, is integrally involved in maternal brain and behavioral responses. When administered intranasally, our pilot data has shown enhanced activation of the striatum, prefrontal cortex and amygdala. The purpose of this renewal grant is to continue and expand upon our investigation of maternal addiction, by conducting a randomized, double-blinded, placebo- controlled, crossover study of intranasal oxytocin on maternal brain responses. A new group of 150 mothers from our two current study sites (Baylor College of Medicine and the Yale Child Study Center) will be enrolled (75 with a history of drug addiction and 75 matched control mothers), along with their 4 to 7-month-old infants, to participate in four study visits over a two-month period. During Visit 1, mothers will complete the Adult Attachment Interview to determine their attachment classification and to identify markers of unresolved trauma. At Visit 2, a videotaped free-play assessment of mother-infant interaction (the CARE-Index), and a modified Still Face Procedure, will be conducted to assess the quality of maternal caregiving and synchrony. During the final two study visits, functional MRI will be used to compare maternal brain responses to infant face cues after receiving either intranasal oxytocin or placebo, comparing own vs. unknown happy and sad faces. We will focus on activation of, and functional connectivity between, the striatum, prefrontal cortex and amygdala, key reward and stress related regions containing oxytocinergic neuronal connections. We will also examine factors that may moderate oxytocin's effect in the brain, including attachment classification, mother-infant synchrony, sensation-seeking or risk-taking behavior, and stress/trauma exposure. This knowledge will contribute significantly to our long-term goal of discovering novel treatment strategies for mothers who suffer from drug dependency and addiction.